Dopamine is an important neurotransmitter in the central nervous system (CNS), and also has several important roles in the peripheral nervous system such as in the control of the supply of blood to the kidneys and in autonomic ganglion transmission.
It is now widely accepted that dopamine receptors in the CNS can be divided into two general categories, designated D-1 and D-2 receptors. The division was originally based on biochemical and pharmacological differences between the two receptor types, but further evidence supporting this division has recently come from study of the molecular biology of dopamine receptors in the CNS. The dopamine D-1 receptor is linked to the enzyme adenylate cyclase through a stimulatory G protein, such that stimulation of this receptor by dopamine or a dopamine D-1 receptor agonist causes an increase in the production of 3',5'-cyclic adenosine monophosphate (cAMP).
The D-2 receptor, on the other hand, also regulates important functional activity within the CNS, although the biochemical events which follow stimulation of this receptor by dopamine or a D-2 receptor agonist are not as well understood. Autoreceptors on dopaminergic neurons which have the pharmacological properties of D-2 receptors are thought to control both the firing rate of these cells as well as the release of dopamine from the nerve terminals. It is also known that stimulation of the D-2 receptors in the intermediate lobe of the pituitary gland causes a decrease in cAMP production and that stimulation of the D-2 receptors on the mammotrophs of the anterior pituitary gland suppresses prolactin secretion. Dopaminergic neurons are also affected by and interact with other neurotransmitter systems in the CNS, as for example D-2 receptors on the cholinergic interneurons in the striatum (one of the components of the basal ganglia) regulating the release of acetylcholine from these cells.
Dopamine involvement has been proposed for several diverse neurological and psychological disorders. One disorder involving dopamine is Parkinson's Disease. Dopamine occurs at high concentration within the nerve terminals in the basal ganglia of the mammalian brain. In the early 1960's, the loss of striatal dopamine was established as a chemical marker of Parkinson's Disease. This deficiency is still thought to be primary to the etiology of the disease state.
L-DOPA (3,4-dihydroxyphenylalanine), which is used in conjunction with a peripheral aromatic amino acid decarboxylase inhibitor and often supplemented with anticholinergic agents, has been shown to be useful in the treatment of Parkinson's Disease. The response to L-DOPA is thought to be a result of the conversion of L-DOPA to dopamine within the striatum, and is linked to stimulation of both the D-1 and D-2 receptors.
The success of L-DOPA therapy has led to the testing of other compounds capable of mimicking the post-synaptic receptor actions of dopamine. Such direct-acting agents might offer the therapeutic advantages of greater potency, increased duration of action, or fewer side effects over L-DOPA. For example, bromocryptine, the direct-acting dopamine agonist most widely used in the treatment of Parkinson's Disease, lowers the amount of L-DOPA required to achieve the maximal therapeutic response and allows for a delay in the onset of L-DOPA therapy. However, the response to bromocryptine alone is not as great as that observed with L-DOPA.
Another disorder in which dopamine has been implicated is schizophrenia. Psychoses are serious psychiatric illnesses characterized by abnormal behavior which may include delusions, hallucinations, violence, mania and serious long-lasting depression. Of these, schizophrenia is the most common, involving disturbance of thought processes, hallucinations and loss of touch with reality. The theory of schizophrenia as a disease of the CNS was first formalized by Kraepelin and Bleuler in the early 1900's. It was not until chlorpromazine was discovered by Delay and Daniker in the early 1950's, however, that drug management of this disease was possible.
The pioneering work of Carlsson and others led to the now widely-held dopamine theory of schizophrenia. According to this theory, schizophrenia is caused by an excess of dopamine in the brain. Several lines of evidence support this hypothesis. For example, chronic abuse of stimulants such as amphetamines, known to enhance dopaminergic activity in the brain, can lead to a paranoid psychosis that is almost indistinguishable from classic paranoid schizophrenia. The mechanism of action proposed for drugs with anti-schizophrenic activity is the blockade by these compounds of the dopamine receptors and, consequently, the prevention of excess receptor stimulation. In the mid 1970's, it was observed that virtually all of the currently used antipsychotic agents could displace radiolabeled haloperidol (a dopamine antagonist) from striatal dopamine receptors with a good correlation between average effective clinical dose and drug binding affinity.
Unfortunately, the currently-available antipsychotic agents frequently produce undesirable side-effects, the most common of which are the so-called extrapyramidal effects that include bizarre involuntary movements and Parkinson-like effects. Sedation and hypotension are also common side-effects. Because of these often severe side-effects and the high incidence of patients unresponsive to currently-available drugs, more potent and more selective agents are needed.
It is also recognized that depressive conditions and related affective disorders result from a reduction in the central nervous system of certain biogenic amine neurotransmitters such as dopamine (D), noradrenaline (NA) and serotonin (5-HT). Affective disorders are characterized by changes in mood as the primary clinical manifestation. Disturbances of mood are the most common psychiatric disorders in adults, with 18-23% of women and 8-11% of men experiencing at least one major depressive episode. Currently-available antidepressant drugs work primarily by raising the levels of the biogenic amine neurotransmitters either by inhibition of the neuronal uptake of the neurotransmitters or by inhibition of the metabolic enzymes responsible for convening the biogenic amines to inactive metabolites. Unfortunately, there are major drawbacks to the use of currently-available agents for treating affective disorders. For example, no antidepressant drug to date has proven to be superior to electroconvulsive shock therapy in the treatment of severe, suicidal depression. Other problems with the use of available drugs are delayed onset of activity, poor efficacy, anticholinergic effects at therapeutic doses, cardiotoxicity, convulsions and the danger of taking a fatal overdose. There also exists a large number of untreated individuals and treatment-resistant patients in need of effective therapy. A role for direct-acting dopamine agonists in antidepressant therapy has been suggested based on the effects observed for several dopamine agonists in various animal models used for predicting antidepressant activity such as the "mouse behavioral despair test".
A role for dopamine has been established in several other neurological functions, such as cognitive function and attention mechanisms. Animal studies implicate dopamine in attention-related behaviors involving search and exploratory activity, distractibility, response rate, discriminability and the switching of attention. A therapeutic role in the treatment of cognitive impairment and attention deficit disorders has therefore been proposed and is under active investigation for compounds which mimic the receptor activity of dopamine.
Dopamine has been also used in the treatment of shock, congestive heart failure and renal failure. Stimulation of the peripheral D-1 receptors causes vasodilation, particularly in the renal and mesenteric vascular beds where large numbers of these receptors are found. The utility of dopamine has been limited, however, by its ability to cause vasoconstriction at higher concentrations, presumably due to its secondary effects on adrenergic receptors and by its emetic effects due to peripheral D-2 stimulation. Agents selective for the peripheral D-1 receptors may offer significant advantages over currently used treatments for these and other related disorders.
Published evidence suggests that dopamine also has a central role in the brain's reward system. For example, it has been reported that animals trained to self-administer cocaine will increase their consumption of this drug after treatment with either a D-1 or a D-2 receptor antagonist. It was proposed that the animals would increase the amount of cocaine administered in order to maintain the elevated dopamine levels responsible for the drugs euphorigenic and reinforcing properties. The dopamine D-1 agonist, SKF 38393, has been reported to decrease food intake by rats presumably by direct action of the drug on neural feeding mechanisms. Because of this interrelationship between dopamine and reward, dopaminergic agents could be useful for the treatment of substance abuse and other addictive behavior disorders including cocaine addiction, nicotine addiction and eating disorders.
Dopaminergic agents such as the compounds of the present invention that mimic the actions of dopamine and show selectivity for the different dopamine receptor subtypes are needed in order to obtain the anticipated physiological responses discussed above, separate from other possibly less desirable effects.
Related 5-hydroxy dopaminergic compounds were reported in U.S. Pat. No. 4,994,486, which is also a continuation-in-part of U.S. application Ser. No. 359,448, and compounds having somewhat related structures to the novel compounds of the instant invention have been disclosed in published European Patent Applications Nos. 321968 and 325963 and in French Patent No. 2,407,212. However, the 1-aminomethyl tetrahydronaphthalene derivatives of EP 0321968 are unsubstituted at the 3-position and are substituted on the amino group with an n-propyl group or an n-propyl and an additional phenoxyethyl group; the 1-aminomethyl tetrahydronaphthalene derivatives of EP 0325963 are substituted on the amino group with an aryl-substituted or heterocycle-substituted alkyl group; and in the 1-aminoalkyl-substituted isochroman and thioisochroman compounds of the French Patent, the amino group of the 1-amino alkyl group must be in a 6-membered ring containing one or two nitrogen atoms and is further substituted with a nitrogen substituent, an aryl group or a benzimidazole group.